Clostridium scindens: A human gut microbe with a high potential to convert glucocorticoids into androgens

Clostridium scindens American Type Culture Collection 35704 is capable of converting primary bile acids to toxic secondary bile acids, as well as converting glucocorticoids to androgens by side-chain cleavage. The molecular structure of the side-chain cleavage product of cortisol produced by C. scindens was determined to be 11 β-hydroxyandrost- 4-ene-3,17-dione (11 β-OHA) by high-resolution mass spectrometry, ¹H and ¹³C NMR spectroscopy, and X-ray crystallography. Using RNA-Seq technology, we identified a cortisol-inducible ( ~ 1,000-fold) operon ( des ABCD) encoding at least one enzyme involved in anaerobic side-chain cleavage. The des C gene was cloned, overexpressed, purified, and found to encode a 20α-hydroxysteroid dehydrogenase (HSDH). This operon also encodes a putative " transketolase" ( des AB) hypothesized to have steroid-17,20-desmolase/ oxidase activity, and a possible corticosteroid transporter ( des D). RNA-Seq data suggests that the two-carbon side chain of glucocorticords may feed into the pentose-phosphate pathway and are used as a carbon source. The 20 α-HSDH is hypothesized to function as a metabolic "rheostat" controlling rates of side-chain cleavage. Phylogenetic analysis suggests this operon is rare in nature and the des C gene evolved from a gene encoding threonine dehydrogenase. The physiological effect of 11 β-OHAD on the host or other gut microbes is currently unknown.